We propose to deliver personalized radiation therapy to patients with locally advanced NSCLC that improves the therapeutic ratio by: (1) increasing local control through FDG PET/CT-guided tumor dose escalation in select patients at high risk of local failure, and (2) limiting pulmonary toxicity through radiation dose avoidance of functiona lung defined on perfusion SPECT/CT. RT is a major treatment option for patients with locally advanced non-small cell lung cancer (NSCLC), but current treatments result in suboptimal tumor control with local failures up to 50%, while carrying substantial risk of toxicity, with grad 3+ pulmonary toxicity seen in 20% of patients. In this proposal, we will explore the fundamental questions of whether radiation dose to functional lung better predicts clinical toxicity than radiation dose to anatomic lung, and whether selective dose escalation to patients at high risk of local failure improves tumor control, while limiting toxicity. The specific aims are: (1) to evaluae toxicity of Functional Lung Avoidance & Response-adaptive Escalation (FLARE) RT in a cohort of locally advanced NSCLC patients; (2) to correlate baseline perfusion imaging parameters with post-treatment radiation pneumonitis; and (3) to predict changes in pulmonary function tests from regional RT dose-induced changes in perfusion imaging parameters. In support of the above aims, patients with locally advanced NSCLC receiving RT will undergo pulmonary function tests (PFTs) and perfusion/ventilation SPECT/CT and PET/CT at baseline, during week 3 of RT and 3 months post-RT. High precision radiation therapy will be administered by combining differential avoidance planning to reduce mean dose to SPECT/CT-defined perfused lung, and differential tumor dose escalation defined on 3 week mid-treatment FDG PET/CT in select patients classified as early FDG PET non-responders. SPECT/CT perfusion image histogram and textural features of lung function heterogeneity will be compared against CT-based dose-volume parameters for correlation to pulmonary toxicity. Spatially mapped changes in SPECT/CT perfusion image uptake will be modeled as a dichotomous dose-response with complete loss of function above dose thresholds, a binned dose-response with partial loss of function in each dose bin, and continuous dose-response at the voxel scale. This project will precisely combine functional lung avoidance and selective dose escalation in an innovative approach that can benefit each segment of a heterogeneous patient population with locally advanced lung cancer. Successful completion will pave the way for efficacy evaluation of FLARE RT in a phase II / III multi-center trial with the potential to significantly improve outcome of patients with locally advanced NSCLC.